S-nitrosylation of cellular proteins has emerged as the key reaction through which nitric oxide exerts its numerous effects inside the body. The growing list of proteins whose activities are regulated by s-nitrosylation include, ion channel proteins, kinases, proteolytic enzymes, transcription factors and proteins involved in energy transduction. In conjunction with s-nitrosylation of these proteins, nitric oxide has been shown to regulate processes and proteins involved in apoptosis, G-protein-coupled receptor based signaling, vascular tone, and inflammatory responses. Whereas s-nitrosylation of target proteins produces the effects of nitric oxide, the denitrosylation pathways terminate the effect of nitric oxide. The enzyme s-nitrosoglutathione reductase (GSNOR) is a member of the alcohol dehydrogenase family and has been shown to be the primary pathway through which cells denitrosylate intracellular proteins. GSNOR catalyzes the denitrosylation of intracellular proteins by the reduction of s-nitrosoglutathione (GSNO). Because of its role in the regulation of the s-nitrosylation of intracellular proteins, GSNOR has become an important target for developing agents that modulate nitric oxide bioactivity.
For example, nitric oxide and the s-nitrosylation de-nitrosylation cycle play an essential role in many pathologies. Various vascular disorders such as heart disease, heart failure, heart attack, hypertension, atherosclerosis, and restenosis are related to nitric oxide activity, and s-nitrosylation states. Similarly, conditions such as asthma and impotence are also linked to varying levels of nitric oxide bioactivity. Nitric oxide activity correlates with the level of GSNO metabolic intermediates in the cell. Nitric oxide activity and GSNO activity levels may also play a role in other disease including Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, stroke, septic shock, cardiogenic shock, endotoxic shock, toxic shock syndrome, systemic inflammatory response syndrome, and other inflammatory diseases. The therapeutic potential of preventing the breakdown of s-nitrosothiols via inhibition of GSNOR has been demonstrated in a mouse model for asthma. Knockout mice lacking the genes for GSNOR were found to resist airway hyperresponsivity due to higher GSNO concentrations in bronchial fluids and diminished tachyphylaxis to β-agonists because of the s-nitrosylation of G-protein coupled receptor kinases.
Given its role in normal and abnormal cell physiology there is a need for compounds that modulate GSNOR activity and\/or method of using those compounds.